ABSTRACT With the increasing prevalence of alcohol use among older adults, it is imperative to better understand the association of alcohol use with risk of mild cognitive impairment (MCI) and brain health in aging. Although many studies suggest that moderate drinking may protect against age-related cognitive impairment and dementia, few studies have demonstrated a protective association of moderate drinking with rates of cognitive decline, or with neuroimaging measures of preserved brain health. Most neuroimaging studies have shown detrimental associations of alcohol with global or regional brain volumes. It is possible that findings of protective associations of moderate drinking on risk of cognitive impairment and dementia stem from inadequate control for confounders since individuals who drink moderately also tend to be of higher socioeconomic status and to engage in other healthy behaviors (such as regular exercise), that are themselves associated with reduced risk of dementia. Conversely, it is also possible that existing studies relating alcohol use to rates of cognitive decline or neuroimaging measures have not used sufficiently sensitive methods to detect subtle, positive associations. Individual differences in genetic predisposition to Alzheimer's disease, or in alcohol metabolizing enzymes, may also obscure effects. The goal of this project, which is responsive to PAR-17-054 ?Leveraging Existing Cohort Studies to Clarify Risk and Protective Factors for Alzheimer's Disease and Related Dementias (R01)? is to clarify the association of alcohol use with cognitive decline, risk of MCI and neuroimaging metrics of brain health in aging by leveraging a unique existing cohort study, the Vietnam Era Twin Study of Aging (VETSA). VETSA is a longitudinal study of ~1500 monozygotic and dizygotic male twin pairs that examines genetic and environmental influences on aging. It contains detailed repeated measures of alcohol use, cognitive function, and brain imaging measures (on a subset of participants), along with a wealth of information on potential confounders. We will determine how alcohol use is associated with rates of cognitive decline and risk of MCI (Aim 1); and with regional brain grey and white matter microstructure and white matter lesion burden (Aim 2). We will determine if observed associations are due to differences in confounding variables, such as socioeconomic status, health status, health behaviors, cognitive reserve or genetic status. Examination of shared heritability between drinking and cognitive/brain outcomes will further inform on potential causal effects of alcohol, as will analyses of discordant twin-pairs. We will also examine whether associations of alcohol with cognitive and brain aging differ by health or genetic status (including polygenic risk for Alzheimer's disease, or for reduced alcohol metabolism; Aim 3). Improved knowledge of whether alcohol is associated with increased or decreased risk of MCI has potential for direct public health impact. This study will inform guidelines for alcohol limits to preserve brain health in aging and will provide for individualized recommendations on alcohol use based upon health and genetic status.